Idiopathic adult growth hormone deficiency

Abstract

GH secretion is controlled by hypothalamic as well as intrapituitary and peripheral signals, all of which converge upon the somatotroph, resulting in integrated GH synthesis and secretion. Enabling an accurate diagnosis of idiopathic adult GH deficiency (IAGHD) is challenged by the pulsatility of GH secretion, provocative test result variability, and suboptimal GH assay standardization. The spectrum between attenuated GH secretion associated with the normal aging process and with obesity and truly well-defined IAGHD is not distinct and may mislead the diagnosis. Adult-onset GHD is mainly caused by an acquired pituitary deficiency, commonly including prior head/neck irradiation, or an expanding pituitary mass causing functional somatotroph compression. To what extent rare cryptic causes account for those patients seemingly classified as IAGHD is unclear. About 15% of patients with adult GHD and receiving GH replacement in open-label surveillance studies are reported as being due to an idiopathic cause. These patients may also reflect a pool of subjects with an as yet to be determined occult defect, or those with unclear or incomplete medical histories (including forgotten past sports head injury or motor vehicle accident). Therefore, submaximal diagnostic evaluation likely leads to an inadvertent diagnosis of IAGHD. In these latter cases, adherence to rigorous biochemical diagnostic criteria and etiology exclusion may result in reclassification of a subset of these patients to a distinct known acquired etiology, or as GH-replete. Accordingly, rigorously verified IAGHD likely comprises less than 10% of adult GHD patients, an already rare disorder. Regardless of etiology, patients with adult GHD, including those with IAGHD, exhibit a well-defined clinical phenotype including increased fat mass, loss of lean muscle mass, decreased bone mass, and enhanced cardiac morbidity. Definition of unique efficacy and dosing parameters for GH replacement and resultant therapeutic efficacy markers in true IAGHD requires prospective study.

Figure 1.

Hypothalamic pituitary control of GH secretion. Hypothalamic GHRH and somatostatin, which traverse the portal vein, somatotroph-specific transcription factors, and negative feedback control of IGF-I all participate in regulatory GH synthesis and secretion. Accurate measurement of pulsatile GH secretion requires ultrasensitive assays. Prop-1, prophet of Pit-1; GHS, GH secretagogs (eg, ghrelin); SRIF, somatostatin. [Reproduced from S. Melmed: Medical progress: acromegaly. N Engl J Med. 2006;355:2558–2573 (81), with permission. © Massachusetts Medical Society.]

Figure 2.

Proportion of patients with various etiologies of GHD in the HYPOCCS surveillance study. The mean percentages for each etiology are shown by 2-yr intervals across the decade. [Modified from S. M. Webb et al: Changing patterns of the adult growth hormone deficiency diagnosis documented in a decade-long global surveillance database. J Clin Endocrinol Metab. 2009;94:392–399 (5), with permission. © The Endocrine Society.]

Figure 3.

Life-table analysis indicating probabilities of initially normal hypothalamic-pituitary-target gland axes remaining normal after radiotherapy (3750–4250 cGy). GH secretion is the most sensitive of the anterior pituitary hormones to effects of external radiotherapy, and GHD precedes development of ACTH, LH, FSH, and TSH hormone deficiencies. [Modified from M. D. Littley et al: Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med. 1989;70:145–160 (82), with permission. © Association of Physicians of Great Britain and Ireland.]

Figure 4.

Summary of side effects reported in double-blind, placebo-controlled studies in healthy subjects of GH administration for 4–12 weeks with median GH dose of 40 μg/kg·/d. Data are presented as a range of percentages of the subjects reporting side effects during GH and placebo administration (20). [Reproduced with permission.]